Collaborative Research: Data-driven integration of biological with in-silico experiments to determine mechanistic effects of N-glycosylation on cellular electromechanical functions

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Completion of this research will describe the fundamental roles for N-glycosylation and its regulation on muscle cell function using a repetitive process blending experimental, statistical, and computational methods. Glycosylation - the process of covalent addition of sugar residues to proteins - is a common modification to proteins involved in cellular communication. Physiological cues regulate the glycosylation process and protein glycosylation impacts electrical and contractile functions of cardiac muscle cells, thereby suggesting a fundamental and dynamic role for glycosylation in muscle cell physiology. The new knowledge gained through this research will be integrated into an interdisciplinary education program at the intersection of experimental and computational muscle cell biology that is aimed at engaging and retaining student scientists, focusing on students/trainees from underrepresented groups. To do so, the following will be developed: 1) A massive open online course on experimental and computational muscle cell biology, 2) Web-based user-friendly myocyte models and analytical algorithms, 3) Initial work on a prototype VR system of myocyte models that enable researchers and students to actively practice, feel, and interact with cellular electromechanical function in real time, and 4) An interactive laboratory experience in cardiovascular physiology for high school students. Recent data suggest a link among regulated glycosylation, electrical signaling, and myocyte contraction. While mechanisms for this putative link remain elusive due to a lack of appropriate models, here, the responsible cellular mechanisms will be determined using an iterative process that combines established biophysical and biochemical techniques with newly developed glycomic methods, rigorous in-silico modeling, and statistical experimental design on a newly created and more appropriate animal model to describe the functional impact of a changing glycome on cardiomyocyte physiology. The impact and significance of describing such a mechanism are broadened by the fact that the glycosylation machinery among species is highly variable. Thus, the differential glycosylation that exists among organisms likely results in modulated protein function that then predictably alters cellular activities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.